Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 20,2026, has been entered.
DETAILED ACTION
The amended claims filed on February 20, 2026, have been acknowledged. Claims 2, 4, 7-10, 12, and 15-17 were cancelled. Claims 1 and 13 were amended. Claims 1, 3, 5-6, 11, 13-14, and 18 are pending and examined on the merits.
Priority
The applicant claims foreign priority from JP2020-191128 filed on November 17, 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received March 28, 2023 and the translated copy received November 17, 2025. Claims 1, 3, 5-6, 11, 13-14, and 18 find support in foreign application JP2020-191128 filed on November 17, 2020.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 6 is dependent on claim 4 which has been cancelled.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3, 5-6, 11, 13-14, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over World Intellectual Property Organization Patent Application No. 2020/067085 (Nakao; US Patent Application No. 2021/0315951 is used as the English translation) and further in view of World Intellectual Property Organization Patent Application No. 2020/136235 (Kleinpeter; referenced in IDS), Flanagan et al. (Vaccine 22: 2894-2903. 2004), Ge et al. (Journal for ImmunoTherapy of Cancer 8: 1-8. 2020; Published March 2020), Elzaouk et al. (Human Gene Therapy 17: 859-870. 2006), and World Intellectual Property Organization Patent Application No. 2019/134049 (Bell; referenced in IDS). This is a new rejection made in response to Applicant’s amendments to claim 1. Any aspect of Applicant’s traversal that is relevant to the rejection as newly written is addressed below.
Regarding claims 1, 6, and 13, Nakao teaches a vaccinia virus deficient in VGF and O1L function encoding the immune regulating genes IL-7 and IL-12 to treat cancer (abstract, paragraphs 0011 and 0063, and Example 1). Nakao teaches the vaccinia virus is from the LC16m0 strain (Example 1 and paragraph 0015).
Nakao does not teach wherein vaccinia virus encodes CCL21.
However, Kleinpeter teaches a vaccinia virus, including LC16m0 strain vaccinia viruses, modified to express a combination of immunomodulatory polypeptides including IL-7, IL-12, and CCL21 and provides examples of two or three different immunomodulatory genes expressed by the same vaccinia virus (abstract, page 18, lines 1-8, page 22, line 4-page 23, line 4, and claims 1-16).
Flanagan teaches that they generated vaccinia viruses encoding secondary lymphoid cytokine (SLC; also known as CCL21) and administered this vaccinia virus to colon cancer tumors, leading to inhibition of tumor growth (abstract).
Ge teaches that they generated vaccinia viruses encoding IL-12 and administered this vaccinia virus to mice with late-stage colon cancer tumors, leading to transformed, immunogenic tumors, inhibition of tumor growth, and improved survival (abstract and Figure 2).
Elzaouk teaches that treating tumors with plasmids encoding IL-12 and plasmids encoding CCL21 reduced tumor growth more than administering either plasmid alone (page 861, column 2, paragraph 2 and Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vaccinia virus encoding IL-12 and IL-7 of Nakao by also encoding CCL21 in the vaccinia virus to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Kleinpeter teaches that vaccinia viruses can incorporate multiple immunomodulatory genes for treating cancer, including IL-7, IL-12, and CCL21, Flanagan and Ge successfully reduce to practice that CCL21 and IL-12 can be encoded in vaccinia viruses to reduce tumor growth and treat cancer, and Elzaouk teaches that expressing IL-12 and CCL21 together in cancer cells improves cancer treatment. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Nakao, as stated supra, teaches that the vaccinia virus can be deficient in VGF and O1L function (paragraph 0063 and Example 1). The specification discloses that when a vaccinia virus deficient in the functions of the two genes, the VGF gene and the O1L gene, infects normal cells, cell growth is not promoted because ERK is not activated in normal cells. As a result, the growth of the vaccinia virus is markedly reduced. However, since the Ras/Raf/MEK/ERK metabolic pathway is abnormally activated in cancer cells and makes up for the function of VGF and O1L to activate ERK in the vaccinia virus, the vaccinia virus can grow. As a result, the vaccinia virus grows in cancer cells and destroys and damages cancer cells (paragraph 0036).
Nakao does not teach wherein the vaccinia virus is deficient in the function of the K2L gene.
However, Bell teaches the CopMD5p3p vaccinia virus. The CopMD5p3p virus has deleted the C2L-F3L genes (this region includes the K2L gene) and the B14R-B29R-ITR genes (Table 1).
Example 9 teaches that they injected the CopMD5p3p virus intravenously into a mouse implanted with cancerous cells and showed that CopMD5p3p is only localized in the tumor while other viruses show off target replication in the tail, muscle, paws and intra-nasal cavity based on a luciferase assay (Example 9 and Figures 15-16). As such, the CopMD5p3p virus grows specifically in tumor cells and does not grow in normal cells. It is worth noting Example 3 of the instant specification used a similar luciferase assay to assess their expression levels in the tumor versus normal cells with their vaccinia viruses. Example 7 shows that the CopMD5p3p virus-controlled tumor growth (i.e. damages cancer cells). Examples 5-6 teach that the CopMD5p3p vaccinia virus causes fusion between cancer cells, allowing the virus to spread to uninfected cells and induce cell death. Bell teaches that the genetically modified vaccinia virus can be from the LC16M0 strain (paragraph 0006). Bell teaches that the virus can be included in a pharmaceutical composition for cancer treatment (paragraphs 00652-00662). Bell teaches that their virus can be used to incorporate exogenous DNA and Example 9 of Bell teaches that the CopMD5p3p virus encodes an exogenous luciferase gene. Bell teaches that their vector exhibits an array of beneficial features, such as improved oncolytic ability, replication in tumors, infectivity, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, and amenability for large scale manufacturing (page 18, paragraph 11 and abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vaccinia virus of the combined teachings of Nakao, Kleinpeter, Falnagan, Ge, and Elzaouk by further deleting the region of genes (C2L-F3L and B14R-B29R-ITR genes) identified by Bell to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Nakao, Flanagan, Ge, and Bell teach that their vaccinia viruses are for treating cancer and Bell teaches that their virus with the additional deletions exhibits an array of beneficial features, such as improved oncolytic ability, replication in tumors, infectivity, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, and amenability for large scale manufacturing. Furthermore, Bell shows that their virus causes fusion between cancer cells which would allow the spread of the virus to uninfected cells and improve the amount of induced cell death in cancer cells. Additionally, the increased number of deleted genes would increase the amount of exogenous DNA that could be incorporated into the vaccinia virus to improve cancer cell killing. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 3, Nakao teaches the vaccinia virus is from the LC16m0 strain (Example 1 and paragraph 0015).
Regarding claim 5, Nakao teaches that their vaccinia virus is an oncolytic virus (paragraph 0033).
Regarding claims 11 and 14, Nakao teaches that their vaccinia virus can be part of a pharmaceutical composition (paragraphs 0008-0021).
Regarding the limitation in claims 11 and 14 “pharmaceutical composition for cancer treatment,” this limitation is considered to be an “intended use” of the claimed composition, and not found to add any structural limitations. See MPEP 2111.02. Nevertheless, Nakao does disclose using their vaccinia virus to treat cancer (paragraphs 0022-0033).
Regarding claim 18, Nakao teaches a method of treating cancer comprising administering the vaccinia virus comprising a polynucleotide encoding interleukin-7 (IL-7) and vaccinia virus comprising a polynucleotide encoding interleukin-12 (IL-12) to a patient (paragraphs 0022-0033). It would have been obvious that this method could be extended to a vaccinia virus encoding IL-7, IL-12, and CCL21.
Response to Arguments
Applicant's arguments filed February 20, 2026, are acknowledged.
First, Applicant argues that claim 1 requires that the IL-12 and CCL21 gene are comprised within the same vaccinia virus while Elzaouk teaches individual plasmids encoding IL-12 and CCL21. Therefore, amended claim 1 is non-obvious over the combination of cited references (page 4, paragraph 9-page 5, paragraph 2).
Applicant's arguments have been fully considered but they are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Furthermore, the rejection is based on the 103 obviousness standard and not anticipation. Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. Therefore, the claim limitations do not have to all be taught within one reference as long as there is some teaching, suggestion, or motivation to combine or modify the teachings of the prior art to produce the claimed invention
Nakao teaches a vaccinia virus deficient in VGF and O1L function encoding the immune regulating genes IL-7 and IL-12 to treat cancer (abstract, paragraphs 0011 and 0063, and Example 1). Nakao teaches the vaccinia virus is from the LC16m0 strain (Example 1 and paragraph 0015).
Kleinpeter teaches a vaccinia virus, including LC16m0 strain vaccinia viruses, modified to express a combination of immunomodulatory polypeptides including IL-7, IL-12, and CCL21 and provides examples of two or three different immunomodulatory genes expressed by the same vaccinia virus (abstract, page 18, lines 1-8, page 22, line 4-page 23, line 4, and claims 1-16).
Flanagan teaches that they generated vaccinia viruses encoding secondary lymphoid cytokine (SLC; also known as CCL21) and administered this vaccinia virus to colon cancer tumors, leading to inhibition of tumor growth (abstract).
Ge teaches that they generated vaccinia viruses encoding IL-12 and administered this vaccinia virus to mice with late-stage colon cancer tumors, leading to transformed, immunogenic tumors, inhibition of tumor growth, and improved survival (abstract and Figure 2)
Elzaouk teaches that treating tumors with plasmids encoding IL-12 and plasmids encoding CCL21 reduced tumor growth more than administering either plasmid alone (page 861, column 2, paragraph 2 and Figure 1).
Bell teaches the CopMD5p3p vaccinia virus. The CopMD5p3p virus has deleted the C2L-F3L genes (this region includes the K2L gene) and the B14R-B29R-ITR genes (Table 1).
Therefore, Nakao successfully reduces to practice that vaccinia viruses can encode multiple immune regulating genes as exogenous genes, including IL-12. Kleinpeter teaches that vaccinia viruses can incorporate multiple immunomodulatory genes for treating cancer, including IL-7, IL-12, and CCL21. Flanagan and Ge successfully reduce to practice that CCL21 and IL-12 can be encoded in vaccinia viruses to reduce tumor growth and treat cancer. Elzaouk successfully reduces to practice that expressing IL-12 and CCL21 together in cancer cells improves cancer treatment. Bell teaches that their virus with the additional deletions exhibits an array of beneficial features, such as improved oncolytic ability, replication in tumors, infectivity, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, and amenability for large scale manufacturing. Furthermore, Bell shows that their virus causes fusion between cancer cells which would allow the spread of the virus to uninfected cells and improve the amount of induced cell death in cancer cells.
As such, the combined teachings of Nakao, Kleinpeter, Flanagan, Ge, Elzaouk, and Bell teach the claimed invention.
Second, Applicant argues that claim 1 requires the K2L gene or the HA gene, or the K2L gene and HA gene are further deleted while Bell only discusses deletion of the K2L gene and not the HA gene. Furthermore, Applicant argues that Bell does not teach that the deletion of K2L gene induces cell death by causing fusion of infected cells. Therefore, amended claim 1 is non-obvious over the combination of cited references (page 5, paragraph 3-page 6, paragraph 1).
Applicant's arguments have been fully considered but they are not persuasive.
Claim 1 requires the K2L gene or the HA gene, or the K2L gene and HA gene are further deleted. As these are in the alternative, only one is required: Either deletion of K2L, deletion of HA, or both. Therefore, claim 1 does not require the deletion of the HA gene as deletion of the K2L gene alone is enough to fulfill the claim limitation. Bell specifically identifies that their CopMD5p3p vaccinia virus, which has deleted the C2L-F3L genes (this region includes the K2L gene) and the B14R-B29R-ITR genes (Table 1), causes fusion between cancer cells, allowing the virus to spread to uninfected cells and induce cell death (Examples 5-6). Therefore, a vaccinia virus with the K2L gene induces cell death by causing fusion of infected cells.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 5-6, 11, and 13-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 9809803 and further in view of World Intellectual Property Organization Patent Application No. 2020/067085 (Nakao; US Patent Application No. 2021/0315951 is used as the English translation), World Intellectual Property Organization Patent Application No. 2020/136235 (Kleinpeter), Flanagan et al. (Vaccine 22: 2894-2903. 2004), Ge et al. (Journal for ImmunoTherapy of Cancer 8: 1-8. 2020), Elzaouk et al. (Human Gene Therapy 17: 859-870. 2006), and World Intellectual Property Organization Patent Application No. 2019/134049 (Bell; referenced in IDS). This is a new rejection made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been fully considered but is unpersuasive for the reasons cited above.
‘803 claims a vaccinia virus which is deprived of functions of the vaccinia virus growth factor (VGF) and O1L, which does not grow in a normal cell but grows specifically in a cancer cell, and which has oncolytic properties of specifically damaging cancer cells, from the LC16m0 strain with oncolytic properties comprising foreign DNA wherein the foreign DNA has immunostimulating effects (i.e. would encompass immune regulating genes) and a pharmaceutical composition comprising the vaccinia virus (claims 1-2, 4-5, and 9).
‘803 is silent as to the exogenous genes used.
However, Nakao teaches a vaccinia virus deficient in VGF and O1L function encoding the immune regulating genes IL-7 and IL-12 that had excellent anti-tumor effects (paragraphs 0011 and 0063 and Example 1).
Therefore, it would have been obvious that IL-7 and IL-12 could be expressed in a vaccinia virus as Nakao has successfully reduced to practice that vaccinia viruses expressing these genes have excellent antitumor activity.
Nakao also teaches that the IL-7 and IL-12 genes can be encoded on separate vaccinia viruses for combined administration wherein the plural vaccinia viruses may be contained in a single pharmaceutical composition (paragraph 0053), Nakao teaches that the pharmaceutical composition comprising the combination of vaccinia viruses wherein a polynucleotide encoding IL-7 and a polynucleotide encoding IL-12 are contained separately in a plurality of vaccinia viruses can be combined and supplied as a kit (paragraphs 0147-0150 and abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified a vaccinia virus of ‘803 to encode IL-12 and IL-7, as identified by Nakao, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Nakao teaches that the these genes improve anti-tumor activity. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of ‘803 and Nakao do not teach wherein the vaccinia virus encodes CCL21.
However, Kleinpeter teaches a vaccinia virus, including LC16m0 strain vaccinia viruses, modified to express a combination of immunomodulatory polypeptides including IL-7, IL-12, and CCL21 and provides examples of two or three different immunomodulatory genes expressed by the same vaccinia virus (abstract, page 18, lines 1-8, page 22, line 4-page 23, line 4, and claims 1-16).
Flanagan teaches that they generated vaccinia viruses encoding secondary lymphoid cytokine (SLC; also known as CCL21) and administered this vaccinia virus to colon cancer tumors, leading to inhibition of tumor growth (abstract).
Ge teaches that they generated vaccinia viruses encoding IL-12 and administered this vaccinia virus to mice with late-stage colon cancer tumors, leading to transformed, immunogenic tumors, inhibition of tumor growth, and improved survival (abstract and Figure 2).
Elzaouk teaches that treating tumors with plasmids encoding IL-12 and plasmids encoding CCL21 reduced tumor growth more than administering either plasmid alone (page 861, column 2, paragraph 2 and Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vaccinia virus encoding IL-12 and IL-7 of the combined teachings of ‘803 and Nakao by also encoding CCL21 in the vaccinia virus to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Kleinpeter teaches that vaccinia viruses can incorporate multiple immunomodulatory genes for treating cancer, including IL-7, IL-12, and CCL21, Flanagan and Ge successfully reduce to practice that CCL21 and IL-12 can be encoded in vaccinia viruses to reduce tumor growth and treat cancer, and Elzaouk teaches that expressing IL-12 and CCL21 together in cancer cells improves cancer treatment. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
‘803, as stated supra, teaches that the vaccinia virus can be deficient in VGF and O1L function which does not grow in a normal cell but grows specifically in a cancer cell, and which has oncolytic properties of specifically damaging cancer cells (claim 1).
‘803 does not teach wherein the vaccinia virus is deficient in the function of the K2L gene.
However, Bell teaches the CopMD5p3p vaccinia virus. The CopMD5p3p virus has deleted the C2L-F3L genes (this region includes the K2L gene) and the B14R-B29R-ITR genes (Table 1).
Example 9 teaches that they injected the CopMD5p3p virus intravenously into a mouse implanted with cancerous cells and showed that CopMD5p3p is only localized in the tumor while other viruses show off target replication in the tail, muscle, paws and intra-nasal cavity based on a luciferase assay (Example 9 and Figures 15-16). As such, the CopMD5p3p virus grows specifically in tumor cells and does not grow in normal cells. It is worth noting Example 3 of the instant specification used a similar luciferase assay to assess their expression levels in the tumor versus normal cells with their vaccinia viruses. Example 7 shows that the CopMD5p3p virus-controlled tumor growth (i.e. damages cancer cells). Examples 5-6 teach that the CopMD5p3p vaccinia virus causes fusion between cancer cells, allowing the virus to spread to uninfected cells and induce cell death. Bell teaches that the genetically modified vaccinia virus can be from the LC16M0 strain (paragraph 0006). Bell teaches that the virus can be included in a pharmaceutical composition for cancer treatment (paragraphs 00652-00662). Bell teaches that their virus can be used to incorporate exogenous DNA and Example 9 of Bell teaches that the CopMD5p3p virus encodes an exogenous luciferase gene. Bell teaches that their vector exhibits an array of beneficial features, such as improved oncolytic ability, replication in tumors, infectivity, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, and amenability for large scale manufacturing (page 18, paragraph 11 and abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vaccinia virus of ‘803 by further deleting the region of genes (C2L-F3L and B14R-B29R-ITR genes) identified by Bell to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because ‘803 and Bell both teach that their vaccinia viruses are for treating cancer and Bell teaches that their virus with the additional deletions exhibits an array of beneficial features, such as improved oncolytic ability, replication in tumors, infectivity, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, and amenability for large scale manufacturing. Furthermore, Bell shows that their virus causes fusion between cancer cells which would allow the spread of the virus to uninfected cells and improve the amount of induced cell death in cancer cells. Additionally, the increased number of deleted genes would increase the amount of exogenous DNA that could be incorporated into the vaccinia virus to improve cancer cell killing. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the limitation in claims 11 and 14 “pharmaceutical composition for cancer treatment,” this limitation is considered to be an “intended use” of the claimed composition, and not found to add any structural limitations. See MPEP 2111.02. Nevertheless, ‘803 and Nakao do disclose using their vaccinia viruses to treat cancer (paragraphs 0022-0033).
Claims 1, 3, 5-6, 11, and 13-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 10888594 and further in view of World Intellectual Property Organization Patent Application No. 2020/136235 (Kleinpeter), Flanagan et al. (Vaccine 22: 2894-2903. 2004), Ge et al. (Journal for ImmunoTherapy of Cancer 8: 1-8. 2020), Elzaouk et al. (Human Gene Therapy 17: 859-870. 2006), and World Intellectual Property Organization Patent Application No. 2019/134049 (Bell; referenced in IDS). This is a new rejection made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been fully considered but is unpersuasive for the reasons cited above.
‘594 claims a vaccinia virus deficient in the VGF and O1L genes from the LC16m0 strain with oncolytic properties encoding IL-7 and IL-12 and a pharmaceutical composition comprising the vaccinia virus (claims 1-4, 7, and 9).
‘594 claims a combination kit comprising: a vaccinia virus comprising a polynucleotide encoding IL-7 and a vaccinia virus comprising a polynucleotide encoding IL-12 and a pharmaceutical composition (claims 17-25)
‘594 does not teach wherein vaccinia virus encodes CCL21.
However, Kleinpeter teaches a vaccinia virus, including LC16m0 strain vaccinia viruses, modified to express a combination of immunomodulatory polypeptides including IL-7, IL-12, and CCL21 and provides examples of two or three different immunomodulatory genes expressed by the same vaccinia virus (abstract, page 18, lines 1-8, page 22, line 4-page 23, line 4, and claims 1-16).
Flanagan teaches that they generated vaccinia viruses encoding secondary lymphoid cytokine (SLC; also known as CCL21) and administered this vaccinia virus to colon cancer tumors, leading to inhibition of tumor growth (abstract).
Ge teaches that they generated vaccinia viruses encoding IL-12 and administered this vaccinia virus to mice with late-stage colon cancer tumors, leading to transformed, immunogenic tumors, inhibition of tumor growth, and improved survival (abstract and Figure 2).
Elzaouk teaches that treating tumors with plasmids encoding IL-12 and plasmids encoding CCL21 reduced tumor growth more than administering either plasmid alone (page 861, column 2, paragraph 2 and Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vaccinia virus encoding IL-12 and IL-7 of ‘594 by also encoding CCL21 in the vaccinia virus to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Kleinpeter teaches that vaccinia viruses can incorporate multiple immunomodulatory genes for treating cancer, including IL-7, IL-12, and CCL21, Flanagan and Ge successfully reduce to practice that CCL21 and IL-12 can be encoded in vaccinia viruses to reduce tumor growth and treat cancer, and Elzaouk teaches that expressing IL-12 and CCL21 together in cancer cells improves cancer treatment. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
‘594, as stated supra, teaches that the vaccinia virus can be deficient in VGF and O1L function claim 1). The specification discloses that when a vaccinia virus deficient in the functions of the two genes, the VGF gene and the O1L gene, infects normal cells, cell growth is not promoted because ERK is not activated in normal cells. As a result, the growth of the vaccinia virus is markedly reduced. However, since the Ras/Raf/MEK/ERK metabolic pathway is abnormally activated in cancer cells and makes up for the function of VGF and O1L to activate ERK in the vaccinia virus, the vaccinia virus can grow. As a result, the vaccinia virus grows specifically in cancer cells and destroys and damages cancer cells (paragraph 0036).
‘594 does not teach wherein the vaccinia virus is deficient in the function of the K2L gene.
However, Bell teaches the CopMD5p3p vaccinia virus. The CopMD5p3p virus has deleted the C2L-F3L genes (this region includes the K2L gene) and the B14R-B29R-ITR genes (Table 1).
Example 9 teaches that they injected the CopMD5p3p virus intravenously into a mouse implanted with cancerous cells and showed that CopMD5p3p is only localized in the tumor while other viruses show off target replication in the tail, muscle, paws and intra-nasal cavity based on a luciferase assay (Example 9 and Figures 15-16). As such, the CopMD5p3p virus grows specifically in tumor cells and does not grow in normal cells. It is worth noting Example 3 of the instant specification used a similar luciferase assay to assess their expression levels in the tumor versus normal cells with their vaccinia viruses. Example 7 shows that the CopMD5p3p virus-controlled tumor growth (i.e. damages cancer cells). Examples 5-6 teach that the CopMD5p3p vaccinia virus causes fusion between cancer cells, allowing the virus to spread to uninfected cells and induce cell death. Bell teaches that the genetically modified vaccinia virus can be from the LC16M0 strain (paragraph 0006). Bell teaches that the virus can be included in a pharmaceutical composition for cancer treatment (paragraphs 00652-00662). Bell teaches that their virus can be used to incorporate exogenous DNA and Example 9 of Bell teaches that the CopMD5p3p virus encodes an exogenous luciferase gene. Bell teaches that their vector exhibits an array of beneficial features, such as improved oncolytic ability, replication in tumors, infectivity, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, and amenability for large scale manufacturing (page 18, paragraph 11 and abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vaccinia virus of ‘594 by further deleting the region of genes (C2L-F3L and B14R-B29R-ITR genes) identified by Bell to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because ‘594 and Bell both teach that their vaccinia viruses are for treating cancer and Bell teaches that their virus with the additional deletions exhibits an array of beneficial features, such as improved oncolytic ability, replication in tumors, infectivity, immune evasion, tumor persistence, capacity for incorporation of exogenous DNA sequences, and amenability for large scale manufacturing. Furthermore, Bell shows that their virus causes fusion between cancer cells which would allow the spread of the virus to uninfected cells and improve the amount of induced cell death in cancer cells. Additionally, the increased number of deleted genes would increase the amount of exogenous DNA that could be incorporated into the vaccinia virus to improve cancer cell killing. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the limitation in claims 11 and 14 “pharmaceutical composition for cancer treatment,” this limitation is considered to be an “intended use” of the claimed composition, and not found to add any structural limitations. See MPEP 2111.02. Nevertheless, ‘594 does disclose that their vaccinia viruses can treat cancer (claim 17).
Claims 1, 3, 5-6, 11, and 13-14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12409198 as applied to claim 1 and further in view of World Intellectual Property Organization Patent Application No. 2020/067085 (Nakao; US Patent Application No. 2021/0315951 is used as the English translation), World Intellectual Property Organization Patent Application No. 2020/136235 (Kleinpeter), Flanagan et al. (Vaccine 22: 2894-2903. 2004), Ge et al. (Journal for ImmunoTherapy of Cancer 8: 1-8. 2020), and Elzaouk et al. (Human Gene Therapy 17: 859-870. 2006). This is a new rejection made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been fully considered but is unpersuasive for the reasons cited above.
‘198 claims a vaccinia virus deficient in the VGF, O1L, and K2L genes from the LC16m0 strain with oncolytic properties comprising foreign DNA wherein the foreign DNA has immunostimulating effects (i.e. would encompass immune regulating genes) and a pharmaceutical composition comprising the vaccinia virus (claims 1-7) and which has oncolytic effects of not growing in normal cells, growing specifically in cancer cells, specifically damaging cancer cells, induces cell fusion between infected cells, enhances a systemic anticancer immune activity, and induces cell death.
‘198 is silent as to the exogenous genes used.
However, Nakao teaches a vaccinia virus deficient in VGF and O1L function encoding the immune regulating genes IL-7 and IL-12 that had excellent anti-tumor effects (paragraphs 0011 and 0063 and Example 1).
Therefore, it would have been obvious that IL-7 and IL-12 could be expressed in a vaccinia virus as Nakao has successfully reduced to practice that vaccinia viruses expressing these genes have excellent antitumor activity.
The combined teachings of ‘198 and Nakao do not teach wherein vaccinia virus encodes CCL21.
However, Kleinpeter teaches a vaccinia virus, including LC16m0 strain vaccinia viruses, modified to express a combination of immunomodulatory polypeptides including IL-7, IL-12, and CCL21 and provides examples of two or three different immunomodulatory genes expressed by the same vaccinia virus (abstract, page 18, lines 1-8, page 22, line 4-page 23, line 4, and claims 1-16).
Flanagan teaches that they generated vaccinia viruses encoding secondary lymphoid cytokine (SLC; also known as CCL21) and administered this vaccinia virus to colon cancer tumors, leading to inhibition of tumor growth (abstract).
Ge teaches that they generated vaccinia viruses encoding IL-12 and administered this vaccinia virus to mice with late-stage colon cancer tumors, leading to transformed, immunogenic tumors, inhibition of tumor growth, and improved survival (abstract and Figure 2).
Elzaouk teaches that treating tumors with plasmids encoding IL-12 and plasmids encoding CCL21 reduced tumor growth more than administering either plasmid alone (page 861, column 2, paragraph 2 and Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vaccinia virus encoding IL-12 and IL-7 of the combined teachings of ‘198 and Nakao by also encoding CCL21 in the vaccinia virus to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Kleinpeter teaches that vaccinia viruses can incorporate multiple immunomodulatory genes for treating cancer, including IL-7, IL-12, and CCL21, Flanagan and Ge successfully reduce to practice that CCL21 and IL-12 can be encoded in vaccinia viruses to reduce tumor growth and treat cancer, and Elzaouk teaches that expressing IL-12 and CCL21 together in cancer cells improves cancer treatment. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the limitation in claims 11 and 14 “pharmaceutical composition for cancer treatment,” this limitation is considered to be an “intended use” of the claimed composition, and not found to add any structural limitations. See MPEP 2111.02. Nevertheless, ‘198 does disclose that their vaccinia viruses can treat cancer (claim 1).
Claims 1 3, 5-6, 11, 13-14, and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6, 8-11, and 13 of copending Application No. 18/246592 and further in view of World Intellectual Property Organization Patent Application No. 2020/067085 (Nakao; US Patent Application No. 2021/0315951 is used as the English translation), World Intellectual Property Organization Patent Application No. 2020/136235 (Kleinpeter), Flanagan et al. (Vaccine 22: 2894-2903. 2004), Ge et al. (Journal for ImmunoTherapy of Cancer 8: 1-8. 2020), and Elzaouk et al. (Human Gene Therapy 17: 859-870. 2006). This is a new rejection made in response to Applicant’s amendments to claim 1. Applicant’s traversal has been fully considered but is unpersuasive for the reasons cited above.
‘592 claims an oncolytic vaccinia virus of the LC16m0 strain with nucleotides 26240-34314 or 23767-32499 deleted (these regions include the K2L gene, also known as 035L gene) deleted and encoding an exogenous DNA with an immune activating effect (i.e. would encompass immune regulating genes) that does not grow in normal cells, but grows in cancer cells and damages cancer cells, a pharmaceutical composition comprising the vaccinia virus, and a method of treating cancer by administering the virus (claims 6, 8-11, and 13). The instant specification discloses that loss of K2L leads to fusion which would induce cell death in cancer cells (paragraph 0021).
‘592 is silent as to the exogenous genes used.
However, Nakao teaches a vaccinia virus deficient in VGF and O1L function encoding the immune regulating genes IL-7 and IL-12 that had excellent anti-tumor effects (paragraphs 0011 and 0063 and Example 1).
Therefore, it would have been obvious that IL-7 and IL-12 could be expressed in a vaccinia virus as Nakao has successfully reduced to practice that vaccinia viruses expressing these genes have excellent antitumor activity.
Nakao also teaches that the IL-7 and IL-12 genes can be encoded on separate vaccinia viruses for combined administration wherein the plural vaccinia viruses may be contained in a single pharmaceutical composition (paragraph 0053), Nakao teaches that the pharmaceutical composition comprising the combination of vaccinia viruses wherein a polynucleotide encoding IL-7 and a polynucleotide encoding IL-12 are contained separately in a plurality of vaccinia viruses can be combined and supplied as a kit (paragraphs 0147-0150 and abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified a first vaccinia virus of ‘198 to encode IL-12 and a second vaccinia virus of ‘803 to encode IL-7, as identified by Nakao, to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Nakao teaches that the these genes improve anti-tumor activity and that they can be administered in separate vaccinia viruses. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The combined teachings of ‘592 and Nakao do not teach wherein vaccinia virus encodes CCL21.
However, Kleinpeter teaches a vaccinia virus, including LC16m0 strain vaccinia viruses, modified to express a combination of immunomodulatory polypeptides including IL-7, IL-12, and CCL21 and provides examples of two or three different immunomodulatory genes expressed by the same vaccinia virus (abstract, page 18, lines 1-8, page 22, line 4-page 23, line 4, and claims 1-16).
Flanagan teaches that they generated vaccinia viruses encoding secondary lymphoid cytokine (SLC; also known as CCL21) and administered this vaccinia virus to colon cancer tumors, leading to inhibition of tumor growth (abstract).
Ge teaches that they generated vaccinia viruses encoding IL-12 and administered this vaccinia virus to mice with late-stage colon cancer tumors, leading to transformed, immunogenic tumors, inhibition of tumor growth, and improved survival (abstract and Figure 2).
Elzaouk teaches that treating tumors with plasmids encoding IL-12 and plasmids encoding CCL21 reduced tumor growth more than administering either plasmid alone (page 861, column 2, paragraph 2 and Figure 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the vaccinia virus encoding IL-12 and IL-7 of the combined teachings of ‘592 and Nakao by also encoding CCL21 in the vaccinia virus to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to modify with a reasonable expectation of success because Kleinpeter teaches that vaccinia viruses can incorporate multiple immunomodulatory genes for treating cancer, including IL-7, IL-12, and CCL21, Flanagan and Ge successfully reduce to practice that CCL21 and IL-12 can be encoded in vaccinia viruses to reduce tumor growth and treat cancer, and Elzaouk teaches that expressing IL-12 and CCL21 together in cancer cells improves cancer treatment. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding the limitation in claims 11 and 14 “pharmaceutical composition for cancer treatment,” this limitation is considered to be an “intended use” of the claimed composition, and not found to add any structural limitations. See MPEP 2111.02. Nevertheless, ‘592 does disclose using their vaccinia viruses to treat cancer (claim 13).
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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